Although osteocytes make up over 90% of all bone cells, little is known about their function compared to other bone cells, the osteoblast and the osteoclast. The osteocyte is the cell ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation and bone resorption. However, the role of osteocytes in modulating strain effects on bone modeling and remodeling is unclear. This Program Project Grant was initiated to develop a team approach to determine the function of osteocytes and response to mechanical strain. The hypothesis to be tested is that osteocytes sense and respond to mechanical strain and in turn send signals that result in either bone loss, remodeling, modeling, or pathologic repair. The mechanisms whereby osteocytes translate mechanical strain into signals include intracellular and extracellular signaling and the expression of genes necessary and specific for osteocyte function. The specific aims of the program project are: 1) To determine the levels of mechanical strain sensed by the osteocyte that result in change of bone mass, 2). To determine the role of E11 in the formation and function of osteocytic dendritic processes, 3) To determine the function and regulation of hemichannels in osteocytes, 4) To determine the function of Dmp1 in osteocytes, and 5). To correlate magntitude of strain with gene expression with biological response. Novel approaches to accomplish these specific aims include the use of an osteocyte-like cell line, primary osteocytes expressing a fluorescent reporter, the use of bioengineering techniques to measure strain sensed by individual osteocytes, transgenic technology, novel means of imaging the osteocyte lacuno-canalicular system, fluorescent image analysis to examine gene expression in single cells and targeted deletion of genes in osteocytes in vivo to examine genes regulated by mechanical strain. This program project is composed of investigators with specific talents, training and expertise in the areas of molecular biology, biochemistry, cell biology and bioengineering who together work in a multidisciplinary manner to integrate, improve, and expand approaches to examine osteocyte function and response to strain. Knowledge gained from the accomplishment of these specific aims will be applied to the prevention and treatment of bone loss due to immobilization, space flight, microdamage, and disease states such as osteoporosis.